Kinases are a large family of cellular proteins involved in signal transduction of cascades which control cell growth and death, survival, migration, differentiation, gene expression, metabolism, protein synthesis and cell cycle regulation. A common mechanism by which these signals are transmitted is reversible phosphorylation, which induces conformational changes is these enzymes and alters their structure and function. The entire kinase genome discovered so far incorporates over 500 individual proteins and their isoforms. Different branches of this genomic tree have been characterized into groups specific for phosphorylating either serine/threonine residues or tyrosines. Some kinases exhibit dual specificity, capable of substrate phosphorylation of tyrosine as well as serine/threonines. Further differentiation can be made in terms of their location in cells. Transmembrane receptor protein kinases exhibit an extracellular domain, capable of ligand binding. These ligand binding mechanisms trigger activation of the kinase catalytic domain which initiates a cascade of signals that controls intracellular functions. Examples of a receptor protein kinase are growth factors such as EGF, FGF, PDGF and IGF. Nonreceptor protein kinases can be found in many compartments of a cell from inner-cell surface membranes to the cell nucleus. One example of a nonreceptor protein kinase is the mitogen activated protein kinase (MAPK) which regulates a pathway, which is important in cell signaling initiated on the exterior cell surfaces via growth factors, for example, VEGF, or hormones, and extending to the cell nucleus by activating transcription factors. These nuclear factors in turn control gene expression in the regulation of cell cycle progression and ultimately cell proliferation, and differentiation.
The MAPK cell signaling pathway is important for drug targeting as this path impinges on nearly all functional hallmarks of cancer cells such as immortalization, growth factor independent proliferation, insensitivity to growth inhibitory signals, metastasis, blood vessel attraction, evasion of apoptosis, and other functional hallmarks. Inappropriate activation though mutation of this molecule is associated with nearly 30% of all human cancers. In general, the inhibition of disregulated kinases such as Ras, PI3K and Raf is an important approach to discover novel treatments for cancer and other diseases. One approach is the discovery of small molecules capable of binding either to the kinase catalytic domain or a regulatory domain in order to modulate the function of protein kinases. Important in this respect is to discover molecules which inhibit a specific signaling path with a high degree of selectivity and a potency within a practical therapeutic window. While significant progress has been made in developing various compounds for the treatment of cancer and inflammatory diseases, there remains a need for specific chemical structures capable of modulating protein kinases, whose disregulated function has been implicated in these diseases.